PROJECT SUMMARY The high degree of comorbidity between substance use disorder (SUD) and post-traumatic stress disorder (PTSD) in the US population suggests that similar underlying mechanisms contribute to both disorders such that having one disorder may predispose one to develop the other. A study of a mostly African-American urban civilian population found that their levels of cocaine use highly correlated with levels of childhood abuse and PTSD symptoms. This suggests that childhood abuse, cocaine addiction, and PTSD interact in minority populations and likely contribute to worse outcomes and health disparities. The vast majority of animal models examine cocaine use and PTSD separately. However, to be able to design better treatment plans for real-life clinical scenarios, we need to understand how these two disorders interact. In this project, we propose to combine animal models of child abuse and neglect with models of cocaine abuse and PTSD to examine to what degree one condition affects the other and to examine whether exposure to cocaine at different developmental stages increases the severity of PTSD-like phenotypes. Our central hypothesis is that developmental stress and cocaine abuse interact to increase the susceptibility to and worsen the severity of PTSD-like symptoms after trauma exposure in adulthood by altering overlapping neuronal circuits. Substance abuse often begins during adolescence, during which time the prefrontal circuits and hippocampal modulation of behavior is still being refined. Therefore, early life stress and adolescent cocaine exposure could alter hippocampal modulation of conditioned fear, potentially leading to increased susceptibility to more severe PTSD-like behaviors in adulthood. To begin to address these issues, in Aim 1, we will first evaluate whether early life neglect and adolescent cocaine use interact to increase susceptibility to and generalization of conditioned fear or impair fear extinction in a rat model. In Aim 2, we will evaluate whether fibroblast growth factor-2 mediates the effects of early life neglect and adolescent cocaine use on fear generalization and extinction. In Aim 3, we will evaluate how early life neglect and adolescent cocaine use interact to alter the excitability of the ventral hippocampus-to-infralimbic cortex portion of the fear circuit. Thus, we will examine the effects of developmental stress and cocaine use on PTSD- related behaviors from a behavioral, circuit, cellular, and molecular level. The Research Resources Core will provide essential support for this project, since the completion of this project's aims will require behavioral and molecular analysis.